CN103402992A - Process for preparing sodium salts or potassium salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylate - Google Patents
Process for preparing sodium salts or potassium salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylate Download PDFInfo
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- CN103402992A CN103402992A CN2012800113600A CN201280011360A CN103402992A CN 103402992 A CN103402992 A CN 103402992A CN 2012800113600 A CN2012800113600 A CN 2012800113600A CN 201280011360 A CN201280011360 A CN 201280011360A CN 103402992 A CN103402992 A CN 103402992A
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- 159000000000 sodium salts Chemical class 0.000 title abstract description 4
- XNGNCFNYBYDSQH-UHFFFAOYSA-N 3-hydroxy-5-oxo-2h-furan-4-carboxylic acid Chemical class OC(=O)C1=C(O)COC1=O XNGNCFNYBYDSQH-UHFFFAOYSA-N 0.000 title abstract 2
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 159000000001 potassium salts Chemical class 0.000 title abstract 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000011734 sodium Substances 0.000 claims abstract description 16
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 15
- -1 chloroacetic ester Chemical class 0.000 claims abstract description 14
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 7
- 239000011591 potassium Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 30
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 23
- 239000001103 potassium chloride Substances 0.000 claims description 22
- 235000011164 potassium chloride Nutrition 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 230000018044 dehydration Effects 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 8
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 6
- 101100114697 Danio rerio cpeb1 gene Proteins 0.000 abstract 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 4
- 229910017053 inorganic salt Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 125000005179 haloacetyl group Chemical group 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002085 enols Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- JCGNDDUYTRNOFT-UHFFFAOYSA-N oxolane-2,4-dione Chemical compound O=C1COC(=O)C1 JCGNDDUYTRNOFT-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing sodium salts or potassium salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylate, comprising the reaction of a malonic ester with potassium hydroxide to give the corresponding malonic ester potassium salt of the formula (III), which is then reacted further with a chloroacetic ester to give a compound of the formula (V), followed by a ring closure reaction in which the compound of the formula (V) is reacted with a sodium alkoxide or potassium alkoxide of the formula ZOR1, wherein R1, R2, R3 and K are each as defined in the description.
Description
The present invention relates to by the initial preparation of the third dicarboxylester 4-hydroxyl-2-oxo-DHF-sodium salt of 3-carboxylicesters or method of sylvite.
The preparation of known hydroxyl-2-oxo-DHF-3-carboxylicesters, its corresponding tautomer or an alkali metal salt is usingd and as the purposes (WO2011/018180 of the component of synthesis of biologically active compound; WO2009/036899; J.Chem.Soc., Perkin Trans.1,1985, the 1567 to 1576 pages; Berichte der Deutschen Chemischen Gesellschaft (1911), 44,1759-1765).Yet currently known methods has shortcoming hereinafter described.
WO201I/018180 described the preparation of hydroxyl-2-oxo-DHF-3-carboxylicesters and wherein describe synthetic initial by malonic ester.Malonic ester and halo Acetyl Chloride 98Min. react (referring to reaction scheme 1) under the existence of alkali.After adding water, obtain required 4-hydroxyl-2-oxo-DHF-3-carboxylicesters.Select alkali in order to can make malonic ester take off proton, form thus the enolate of malonic ester, and then by the acetylize of halo Acetyl Chloride 98Min. compound.Suitable alkali is especially formula M (OR
a)
bAlkoxide, wherein M is Na
+, K
+, M
g 2+, b is 1 or 2 and R
aFor methyl or ethyl.Sodium methylate is to be pointed out that preferred.In case cyclization completes, the inorganic salt that namely obtain required product and obtain as by product (, if use sodium alkoxide as alkali, being for example, NaCl).
Reaction scheme 1
As truly likely, especially, when it be NaCl, can only pass through the extremely technology realization of high complexity from reaction mixture, removing inorganic salt, fabulous water-soluble because the compound of formula (P-I) and (P-I ') has.Distillation is infeasible, because the compound of formula (P-I) and (P-I ') decomposes and discharges CO under relatively-high temperature
2.Therefore inorganic salt can't be removed.It is introduced in subsequent reactions and can only the compound of formula (P-I) and/or (P-I ') further reaction after completing, just can remove.
WO2009/036899 has described 4-hydroxyl-2-oxo-2, synthesizing of the salt of 5-dihydrofuran-3-carboxylicesters, it is initial and wherein use chloracetate and pure alkali by malonic ester sylvite, sodium methylate for example, the salt (referring to reaction scheme 2) for preparing corresponding 4-hydroxyl-2-oxo-DHF-3-carboxylicesters.This reaction does not generate any inorganic salt that must bring subsequent reactions into, but should reaction use dimethyl formamide or N,N-DIMETHYLACETAMIDE as solvent, and at first they be expensive, and next is difficult to remove and only can reclaims difficultly.
Reaction scheme 2:
The step 1 of above-mentioned reaction is esterification, and wherein Repone K obtains and needs subsequently from reaction mixture, separating as by product.In step 2, ring-closure reaction occurring and generate required compound (Q-II), and wherein transesterification reaction can occur, make the compound separation of formula (Q-II ').Transesterification reaction in step 2 can contain the R that steric hindrance is arranged by use
fThe alkoxide of group (for example tertiary butyl alkoxide) is inhibited.The compound of formula (Q-IV) is solid, commercially available maybe can by the preparation of known method (referring to J.Am.Chem.Soc.1944, No.66, the 1286th page; EP-A-950653; WO2008/150487).
Described reaction is unfavorable for that technical scale uses, because its malonic ester sylvite by the formula (Q-IV) that exists with solid form of costliness is initial.In the situation that prepared by technical scale, using solid is fundamentally undesirable as initiator, because these solids are difficult to carry out technical finesse and often will change solvent, and the technology very complex that must cause reaction to carry out.
By preparation 4-hydroxyl-2-oxo-2, the currently known methods of the salt of 5-dihydrofuran-3-carboxylicesters or corresponding enol form tautomer is initial, the problem that produces now is to prepare in the mode of cheap and simple these materials, so that the method also can be used for technical scale, prepares required compound.Also wish to find a kind of method, it carries out continuously at least partly and wherein avoids the intricately separation of intermediates.Cheap method be interpreted as meaning those due to initial substance be for example cheapness and/or toxicological harmless and the method that need not any large expenditure can carry out, described method needs less method steps or even in the mode of " one pot reaction ", carries out (namely without separation of intermediates), and/or the sodium salt of required 4-hydroxyl-2-oxo-DHF-3-carboxylicesters or sylvite obtain with sufficiently high productive rate and purity.A kind of like this method is provided also advantageously, and it has conservation of resources, for example wherein consumes energy still less, and/or has selectivity, this means the by product that only forms less degree.
A kind of 4-hydroxyl for preparing general formula (I)-2-oxo-2 have been found at present, 5-dihydrofuran-the sodium salt of 3-carboxylicesters or the method for sylvite, described method has avoided the mode that above-mentioned shortcoming also can be simple and cheap to carry out, especially because it does not need complicated intermediate to separate and/or purifying.The method does not use any solid as initiator yet, can save solvent expensive and inconvenience.The method both can be carried out continuously, also can carry out in batches.
Known hydroxyl-2-oxo-DHF-3-carboxylicesters also can be used as tautomer and exists, and namely the form with 2,4-dioxo tetrahydrofuran (THF)-3-carboxylicesters exists.Any description about hydroxyl-2-oxo-DHF-3-carboxylicesters also comprises corresponding tautomer.
Therefore, the invention provides the 4-hydroxyl of preparation formula (I) hereinafter described-2-oxo-DHF-sodium salt of 3-carboxylicesters or method of sylvite
Wherein Z is sodium or potassium, and R
1Such as hereinafter definition, and as already described, it can following tautomeric form exist:
Therefore, the application relates to the 4-hydroxyl of a kind of preparation formula (the I)-2-oxo-DHF-sodium salt of 3-carboxylicesters or method of sylvite, said method comprising the steps of:
Step (i):
At solvent, in preferred alcohols, especially methyl alcohol or ethanol, make malonic ester and the potassium hydroxide reaction of symmetrical formula (II), potassium hydroxide preferably uses with the form of potassium hydroxide aqueous solution,
Generate the malonic ester sylvite of corresponding formula (III)
Wherein, in formula (II) and formula (III),
R
2For C
1-C
12-alkyl, R
2Preferred C
1-C
4-alkyl, R
2More preferably methyl or ethyl;
Step (ii):
Make the propanedioic acid sylvite of formula (III) and the chloracetate reaction of formula (IV)
Wherein
R
3For C
1-C
12-alkyl, R
3Preferred C
1-C
4-alkyl, R
3More preferably methyl or ethyl, generate the compound of formula V
Wherein
R
2Have the definition of listing in about formula (III), and
R
3Have the definition of listing in about formula (IV),
Step (iii) ring-closure reaction:
Make compound and the formula ZOR of formula (V)
1Sodium alkoxide or pure nak response, wherein
R
1For C
1-C
12-alkyl, R
1Preferred C
1-C
6-alkyl, R
1More preferably ethyl or methyl, and
Z is sodium or potassium, preferred sodium,
After wherein in step (ii), adding chloracetate, reaction mixture carries out azeotropic dehydration.
The malonic ester sylvite of the formula (III) of preparation can be from directly separating the malonic ester of formula (II) in step (i), preferably by being separated, in this case, the malonic ester sylvite of formula (III) is stayed aqueous phase, and malonic ester is in organic phase.
Malonic ester sylvite obtains with a kind of like this purity in step (i), described purity makes malonic ester sylvite without being further purified, namely can be used for step (ii) from after separating reaction mixture.Therefore, described compound does not use with solid form, but uses with solubilized form.According to the present invention, from the water from still existing step (i) of this formula malonic ester sylvite, by the water azeotropic dehydration of the malonic ester sylvite to containing formula (III), remove.Dehydration is until just carry out after adding the chloracetate of formula (IV).Therefore, the reacting body (in substance) in step (ii) carries out.
Azeotropic dehydration is interpreted as meaning to remove and anhydrate by component distillation at this, preferably by means of phase separator and under the existence of the suitable entrainment agent (for example toluene or dimethylbenzene) with water formation azeotropic mixture, carries out.
Except after anhydrating, the compound of unconverted formula (II) can for another reaction with potassium hydroxide, this have formed a large advantage of operate continuously without further aftertreatment.
Method of the present invention is with respect to the advantage of the method that WO2009/036899 describes, in reaction, can save and be difficult to the expensive solvent of removing and reclaiming, for example dimethyl formamide or N,N-DIMETHYLACETAMIDE, and malonic ester sylvite is at no time with isolated in solid form out.
Step (ii) is preferably carried out under the existence of the water as reaction medium of a small amount of (catalytic amount).A small amount of water is interpreted as meaning to count the following water yield based on the gross weight of the reaction mixture after azeotropic dehydration: approximately 0.8 to about 5.0 % by weight.According to the present invention, preferred amount is for approximately 0.8 to about 4.0 % by weight, and approximately 0.8 to about 3.0 % by weight, and approximately 0.8 to about 2.0 % by weight, and approximately 0.8 to about 1.5 % by weight.
Due to the existence of the water of (catalytic amount) on a small quantity, the reaction of step (ii) is significantly accelerated and has produced fully to transform.
The chloracetate of unconverted formula (IV) can be without further aftertreatment for another reaction of the malonic ester sylvite with formula (III) in step (ii), and this has formed a large advantage of operate continuously.
The compound of the formula (V) that obtains in step (ii) obtains with a kind of like this purity, and described purity makes the compound of formula (V) can be without the intermediate separation for step (iii).Yet, preferably make the compound of formula (V) further before reaction, distill, be separated and azeotropic drying.
The suitable solvent that can be used in step (i) is alcohol, especially methyl alcohol and ethanol.Also can use other known alcohol.The consumption of solvent makes reaction mixture during reaction remain good stirring capacity.Advantageously, step (i) is carried out in the mixture of alcohol and mixture, the especially methyl alcohol of water and water or ethanol and water.Usually, by using potassium hydroxide aqueous solution that water is introduced in reaction mixture.If the water deficiency of introducing thus, can add water certainly in reaction mixture.Can change the water yield to be added, and can easily be determined by those skilled in the art.
For the ring-closure reaction of step (iii), can use sodium alkoxide or potassium alcoholate, especially sodium methylate or sodium ethylate arbitrarily.For technology and economic cause, preferred use be dissolved in corresponding alcohol, exist and also commercially available sodium alkoxide or potassium alcoholate (for example being dissolved in the sodium methylate in methyl alcohol) because do not need like this to use any other solvent.
The ring-closure reaction of the reaction of step (i) and step (ii) and step (iii) can carry out under standard pressure.Also can under decompression or pressurization (super-atmospheric pressure), react.
Step (i), (ii) and reaction (iii) are carried out at suitable temperature, described temperature depends on the substrate that uses.Suitable temperature simply mode is determined by routine test.
Step (i) can be for example, and at approximately-20 ℃ to approximately 20 ℃, preferred approximately-10 ℃ are extremely approximately carried out in the scope of 10 ℃.Particularly preferably in approximately-5 ℃, extremely approximately in the scope of 0 ℃, carry out this reaction, preferably under standard pressure, carry out.
Step (ii) can be for example, at approximately 20 ℃ to approximately 200 ℃, preferred approximately 60 ℃ to approximately in the scope of 150 ℃, carrying out.Particularly preferably in approximately 80 ℃ to approximately in the scope of 150 ℃, carrying out this reaction, preferably under standard pressure, carry out.
Step (iii) can be for example, at approximately 20 ℃ to approximately 120 ℃, preferred approximately 20 ℃ to approximately in the scope of 100 ℃, carrying out.Particularly preferably in approximately 20 ℃ to approximately in the scope of 80 ℃, carrying out this reaction, preferably under standard pressure, carry out.
In the step (i) of the inventive method, (ii) with (iii), the mol ratio of the compound of the compound of formula (II) and the mol ratio of potassium hydroxide or formula (III) and the compound of formula (IV) or compound and the alkali metal alcoholates ZOR of formula (V)
1Mol ratio can in wide scope, change.They are usually without any restriction.
In step (i), when the mol ratio of the compound of formula (II) and potassium hydroxide, approximately 1.1 to about 10 scope, 1.5 be approximately especially favourable in about 6 scope the time.Preferably, according to the present invention, this mol ratio is in about 1.8 to 3 scope.
In step (ii), when the mol ratio of the compound of the compound of formula (IV) and formula (III), approximately 10 to about 1 scope, 8 be approximately especially favourable in about 1 scope the time.Preferably, according to the present invention, this mol ratio is in about 6 to 1 scope.
In step (iii), when the mol ratio of the compound of formula (V) and alkali metal alcoholates, approximately 0.9 to about 10 scope, 1 be approximately especially favourable in about 5 scope the time.Preferably, according to the present invention, this mol ratio is in about 1 to 2 scope.
Description about alkyl comprises branching or nonbranched alkyl.C
1-C
12The example of-alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl butyl, 1-ethyl propyl, 1,2-dimethyl propyl, hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, positive ten-alkyl and dodecyl.In these alkyl, C
1-C
6-alkyl is particularly preferred.Especially preferred C
1-C
4-alkyl, especially methyl and ethyl.
By following examples, describe the present invention in detail, but described embodiment should not explain to limit mode of the present invention.
Preparation Example
Buy and execute example 1
The preparation of 4-(methoxycarbonyl)-5-oxo-DHF-3-sodium alkoxide and 4-(ethoxy carbonyl)-5-oxo-DHF-3-sodium alkoxide
Step (i): the ethanol of the diethyl malonate of charging 481g (3.00mmol) and 300g and be cooled to-5 ℃ at first.At-5 ℃ under 0 ℃, in 2 hours to the 25%KOH aqueous solution that is metered into 337g (1.50mmol) in this mixture.Under 0 ℃, stirred this mixture 30 minutes, then ethanol is removed in distillation under 30 ℃.Under 5 ℃, separate two-phase, exist the upper organic phase of unconverted diethyl malonate can be directly used in further hydrolysis reaction.
Step (ii): under reduced pressure in the 30-50 ℃ of ethyl chloroacetate azeotropic dehydration by water and 458g (3.75mol).At the water (0.8 % by weight, based on the quality of reaction mixture) of the ethyl chloroacetate that adds another part 458g (3.75mol) and 9.4g, as after reaction medium, be about to mixture and be heated to 105 ℃ and at this temperature, stirred again 2.5 hours.Subsequently, first ethyl chloroacetate is removed in distillation under 60-80 ℃, yet after adding the water of 375g, azeotropic is removed the ethyl chloroacetate of residual content.After being cooled to 20 ℃, remove water.
Step (iii): under reduced pressure in the 50-70 ℃ of azeotropic drying of the dimethylbenzene by organic phase and 50g, then, under 40-50 ℃, sneaked into the methanol solution of 30% sodium methylate of 270g (1.50mol) in 1 hour.Then heated mixt to 65 ℃, heated 2 hours, then be cooled to 20 ℃, at this temperature, stirred 1 hour and filter.Residue methanol wash and the drying under reduced pressure of 60g as displacement washing liquid.Obtained 209g4-(methoxycarbonyl)-5-oxo-DHF-3-sodium alkoxide and 4-(ethoxy carbonyl)-5-oxo-DHF-3-sodium alkoxide is the mixture of 7:3.Based on the potassium hydroxide that uses, this is equivalent to 76% isolated yield.
1H NMR (D
2O, 298K) δ: 3.73s (3H), 4.42s (2H) [main ingredient];
1.30t (3H), 4.23q (2H), 4.42s (2H) [accessory constituent]
Claims (7)
1. the 4-hydroxyl of preparation formula (the I)-2-oxo-DHF-sodium salt of 3-carboxylicesters or method of sylvite
Wherein
Z is sodium or potassium, and
R
1For C
1-C
12-alkyl,
Said method comprising the steps of:
Step (i):In solvent, make malonic ester and the potassium hydroxide reaction of symmetrical formula (II),
Generate the malonic ester sylvite of corresponding formula (III)
Wherein, in formula (II) and formula (III),
R
2For C
1-C
12-alkyl;
Step (ii):Make the propanedioic acid sylvite of formula (III) and the chloracetate reaction of formula (IV)
Wherein
R
3For C
1-C
12-alkyl,
Generate the compound of formula V
Wherein
R
2Have the definition of listing in about formula (III), and
R
3Have the definition of listing in about formula (IV),
Step (iii):Make compound and the formula ZOR of formula (V)
1Sodium alkoxide or pure nak response, wherein
R
1For C
1-C
12-alkyl, and
Z is sodium or potassium,
After wherein in step (ii), adding chloracetate, reaction mixture carries out azeotropic dehydration.
2. the process of claim 1 wherein in step (i) use potassium hydroxide aqueous solution and wherein the solvent in step (i) be alcohol.
3. claim 1 or 2 method, wherein, the conversion of step (i) in a single day completes, by the malonic ester sylvite of formula (III) by the mode that is separated from the unconverted malonic ester of formula (II), separating, then for step (ii).
4. the process of claim 1 wherein, in step (ii), after carrying out azeotropic dehydration again to the water that adds 0.8 to 5.0 % by weight in reaction mixture.
5. the method for claim 4, wherein step (ii) body carries out.
6. the method for claim 1 to 5 any one, wherein, in step (iii), use sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.
7. the method for claim 6, wherein sodium methylate or potassium methylate are dissolved in methyl alcohol and exist, and sodium ethylate or potassium ethylate are dissolved in ethanol and exist.
Applications Claiming Priority (5)
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| US201161448805P | 2011-03-03 | 2011-03-03 | |
| US61/448,805 | 2011-03-03 | ||
| EP11156806.9 | 2011-03-03 | ||
| EP11156806 | 2011-03-03 | ||
| PCT/EP2012/053418 WO2012117015A1 (en) | 2011-03-03 | 2012-02-29 | Process for preparing sodium salts or potassium salts of 4-hydroxy-2-oxo-2,5-dihydrofuran-3-carboxylate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636571A (en) * | 1983-06-13 | 1987-01-13 | National Distillers And Chemical Corporation | 4-carbalkoxy-2-ethyl-2,3-dihydrofurans |
| CN101801948A (en) * | 2007-09-18 | 2010-08-11 | 拜尔农作物科学股份公司 | Method for producing 4-aminobut-2-enolides |
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| DE19817935A1 (en) | 1998-04-17 | 1999-11-04 | Mannesmann Ag | Pick-up device for load pick-up and delivery of load units |
| DE19817101A1 (en) | 1998-04-17 | 1999-10-21 | Degussa | Process for the preparation of potassium monoethyl malonate |
| US8338635B2 (en) | 2007-05-31 | 2012-12-25 | Satomi Niwayama | Synthesis of half esters |
| MX2012001675A (en) | 2009-08-11 | 2012-03-06 | Bayer Cropscience Ag | Method for producing 2,4-dioxotetrahydrofurane-3-carboxylates. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4636571A (en) * | 1983-06-13 | 1987-01-13 | National Distillers And Chemical Corporation | 4-carbalkoxy-2-ethyl-2,3-dihydrofurans |
| CN101801948A (en) * | 2007-09-18 | 2010-08-11 | 拜尔农作物科学股份公司 | Method for producing 4-aminobut-2-enolides |
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| IL228208A (en) | 2015-11-30 |
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| JP2014506906A (en) | 2014-03-20 |
| DK2681202T3 (en) | 2015-01-26 |
| EP2681202A1 (en) | 2014-01-08 |
| US20140148604A1 (en) | 2014-05-29 |
| BR112013022280A2 (en) | 2020-09-01 |
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| US9056848B2 (en) | 2015-06-16 |
| CN103402992B (en) | 2016-06-15 |
| KR101873082B1 (en) | 2018-06-29 |
| KR20140015350A (en) | 2014-02-06 |
| EP2681202B1 (en) | 2014-10-22 |
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| BR112013022280B8 (en) | 2021-06-08 |
| WO2012117015A1 (en) | 2012-09-07 |
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